INTRODUCTION: Nonbenzodiazepine (non-BZD) sedative hypnotics (NBSH) refer to non-BZD sedatives that act as BZD receptor agonists such as zolpidem, zaleplon, and eszopiclone. Today, there is a high prevalence of insomnia with or without concurrent obstructive sleep apnea (OSA). Our goal was to study how NBSH use impacts the baseline apnea–hypopnea index (AHI) in patients with or without OSA.METHODS: PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases were searched.RESULTS: Seventeen studies comprising a cumulative total of 2099 patients were identified in the last 30 years (between 1988 and 2017) that evaluated the effect of NBSH on respiratory parameters during sleep. The AHI mean (M) ± standard deviation (SD) in NBSH group was 13.17 ± 16.27 versus 15.94 ± 19.31 (mean difference [MD]-95% confidence interval [CI], 2.77 [1.463–4.076]). Six studies (100 patients) compared zolpidem with either placebo or no medication and demonstrated an AHI MD of −0.61 events/h (95% CI − 1.94, 0.71), overall effect Z = 0.9, P = 0.36. Four studies (362 patients) compared eszopiclone with placebo and demonstrated an AHI MD of −5.73 events/h0 (95% CI − 8.90, −0.2.57). Two large studies (979 patients) compared both zolpidem and eszopiclone to no medication and found AHI MD of −1.66 events/h (95% CI − 5.87, 0.2.55).CONCLUSIONS: The majority of patients using NBSH did not develop any worsening of existing AHI, when using NBSH, regardless of their baseline AHI values (mild, moderate, severe, or no OSA). On average, the AHI improved minimally with NBSH and eszopiclone showed the largest difference in AHI with an MD of −5.73 events/h.

Nonbenzodiazepine (non-BZD) sedative hypnotics (NBSH) are drugs that are structurally non-BZD compounds that act as BZD receptor agonists and bind preferentially to the ω1-BZD receptor of the BZD receptor component of the GRSC (gamma-aminobutyric acid [GABA]-receptor-mediated chloride ionophore supramolecular complex).[1] NBSH group of medications includes imidazopyridine zolpidem, cyclopyrrolone zopiclone, S-isomer of racemic zopiclone called eszopiclone, and pyrazolopyrimidine zaleplon. These medications differ pharmacokinetically in their therapeutic half-lives. Zolpidem is one of the most common and widely used NBSHs today, in an era where the use of prescription medications for use in insomnia is on the rise.[2] Zolpidem is chemically an imidazopyridine (N, N,6-trimethyl-2-[4-methylphenyl] imidazo (1,2-a) pyridine-3-acetamide hemitartrate) that binds selectively and with high affinity to the α-1-containing GABAA receptors but with much lower affinity to α-2 and α-3 and not at all to α-5.[3] This is in contrast to zopiclone and eszopiclone that have similar affinity for GABA receptors containing α1, α2, α3, and α5 subunits.[4] Currently, NBSH medications are US Food and Drug Administration approved for the treatment of insomnia in adults only. The limited clinical data on zolpidem in children has raised concerns about lack of efficacy and side effects (dizziness, headache, and hallucination).[5]

The association between obstructive sleep apnea (OSA) and insomnia is strong and often interdependent. Insomnia-related complaints are predominant in 39%–58% of patients with OSA; and reciprocally a substantial proportion (29%–67%) of patients with insomnia have some severity of sleep apnea (as defined by apnea–hypopnea index [AHI] of 5 events/h or higher).[6] Given NBSH like zolpidem are one of the most commonly prescribed sedative-hypnotics, it would be prudent to determine if this class of medications can ameliorate the severity of existing sleep-disordered breathing or even iatrogenically worsen existing AHI (in a nonsleep apneic patient) in the range of clinical sleep apnea. To date, only one meta-analysis has been conducted that evaluated the effect of NBSH on sleep apnea severity.[7] That meta-analysis included eight studies with a cumulative total of 448 patients. Since this was an early meta-analysis, it did not capture the results of studies conducted in the last 6 years. Given the recent increase in prescription of NBSH medications, we felt necessary that the pertinent research data be revisited, revised, and updated. We present a robust review comprised of 17 studies conducted over the last 30 years including a total of 2099 patients to comprehensively assess the effects of NBSH on the existing AHI in patients with and without prior diagnosis of sleep-disordered breathing.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24]

Methods

Search strategy

The following search strategy was used in PubMed/MEDLINE, other versions were used in the additional databases after being tailored to the specific requirements: (hypnotics odds ratio [OR] sedatives OR “non-BZD hypnotics” OR “NBSH” OR non-BZD OR pyrazolopyrimidine OR zaleplon OR eszopiclone OR cyclopyrrolone OR zopiclone OR imidazopyridine OR zolpidem) AND (”sleep apnea” OR “sleep apnoea” OR “AHI” OR “apnoea-hypopnoea index” OR “respiratory disturbance index [RDI]” OR AHI OR RDI). Please refer to [Figure 1] for details.

Inclusion criteria: (1) All studies that included patients being administered an NBSH medication followed by determination or discussion of the subsequent AHI compared to nonusers or placebo treatment. (2) Sleep studies conducted in-lab or at home to determine AHI. (3) Studies including patients treated with NBSH as a pretreatment to calibrate continuous positive airway pressure (CPAP) titration for a diagnosis of OSA. (4) Studies including patients treated with NBSH for insomnia, with or without concurrent diagnosis of OSA. (5) Studies including patients treated with NBSH for idiopathic central sleep apnea (ICSA).

Based on the criteria described above 17 studies were included in this meta-analysis.[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] These represented a cumulative sample size of 2099 patients. The results are representative of global AHI outcomes providing data for patients exposed to different varieties and dosages of NBSH medications. Twelve studies were conducted in the United States, and one study from each of the following countries: Canada, France, Italy, Brazil, and Australia. Three studies used the definition for hypopnea at ≥3% oxygen desaturation from preevent baseline while eight studies used ≥4% oxygen desaturation from preevent baseline to categorize them as hypopneas. The remaining studies did not mention, what hypopnea definition was used to arrive at the final calculation for AHI. The majority of the identified studies were randomized, double-blind cross-over studies, whereas four studies were retrospective reviews. Ten studies had 100% enrollees with OSA, one study had 82% patients with OSA, and at least two studies had no enrollees with OSA. Five studies found NBSH use could increase the final AHI; four studies found NBSH use could decrease the final AHI and eight studies found NBSH use did not affect the final AHI.

At least two studies were composed of all participants devoid of baseline OSA where baseline AHI was <5 events/h. Quera-Salva et al. studied “heavy snorers” without baseline OSA, while Steens et al. studied chronic obstructive pulmonary disease patients without OSA. When compared to placebo, both these studies observed at best a marginal, few indices rise in baseline AHI with use of zolpidem that was either statistically significant (Quera-Salva et al.) or insignificant (Steens et al.). Despite this nominal rise in AHI, most patients did not develop polysomnographically validated OSA due to use of zolpidem.

At least ten studies claimed 100% participants having baseline OSA. Majority of these studies found no significant change in AHI (Carter et al., Rosenberg et al., Park et al., Berry et al., and Coyle et al.) or even a statistically significant decrease in AHI (Eckert et al. and Collen et al.) when compared to placebo/no medication cohort. Of note, Berry et al. and Rosenberg et al. also happened to be studies with least heterogeneity. Only one study (Loh et al.) found a statistically significant increase in AHI following use of NBSH compared to no medication. Of note, Loh et al. data were presented as a meeting abstract. The authors here conceded that the rise in AHI noted could have been partly related to selection bias, given that the providers, who prescribed NBSH to their patients had a different referral pattern than providers, who did not prescribe any hypnotics to their patients. The study with the largest sample size in this meta-analysis was that of Smith et al. with 579 participants, and majority of the participants had OSA. This study concluded that use of NBSH during polysomnogram does not change the mean AHI. In addition to these nine studies, another study in this meta-analysis was that of Quadri et al. who studied patients with ICSA. They found that in patients with ICSA, with use of NBSH, central apneas and hypopneas decreased significantly, without any significant worsening of OSA.

Effect of nonbenzodiazepines sedative hypnotics on apnea–hypopnea index including all patient populations regardless of comorbidities

NBSH use most likely results in no numerically prominent or statistically significant changes in AHI for the vast majority of patients, while in some participants, it may increase or decrease the baseline AHI. [Figure 4] provides some hypothetical possibilities as to how NBSH medications could alter the baseline AHI.

Few studies reported increased AHI on night patients were exposed to NBSH compared to placebo or no use of NBSH medication. Like BZDs, could NBSH lead to relaxation of upper airway muscles leading to elevation of AHI as their sedative effects permeate?[25] This is likely not the case, especially when NBSH involved is zolpidem. While the selective binding of zolpidem on the α-1-containing GABAA receptors is not absolute, its strong preference and affinity for the above receptor subunit may explain the relative absence of myorelaxant effect related to this drug. Unlike classical BZDs where sedative and myorelaxant effects occurring at any given dose are mutual and inextricable (given almost equal binding to all receptor subunits), in case of zolpidem, the preferential and selective binding to α-1-subunit of GABAA receptors ensures that the sedative/hypnotic effect kicks in at a much lower dose than do the other pharmacological effects attributed to BZD-site action such as their myorelaxant properties.[26]

First of all, the most studies that arrived at this conclusion conceded that the iatrogenic numerical rise in AHI was small and/or insignificant (Cirignotta et al., Steens et al., and Lettieri et al. (2005)). Second, selection bias at least in part may be contributing to the elevated AHI reported with NBSH use. This was exemplified in the study by Loh et al. as discussed above. Third, up to 15% patients with OSA will demonstrate considerable night-to-night variability in their recorded AHI, which could have affected the final AHI on the night of NBSH administration.[27] Finally, a higher proportion of supine sleep or higher proportion of rapid eye movement sleep on the night of NBSH medication administration could also lead to a higher final AHI on such nights.[28] Of note, one study (in case of Quera-Salva et al.) showed a small, yet statistically significant rise in AHI with use of zolpidem when compared to placebo. In this study, they even noticed that one patient had a RDI that was “almost pathological with zolpidem” (RDI of 10 events/h), whereas in the remaining participants, the RDIs were far from being abnormal with zolpidem (RDI <5 events/h). One possibility is the development of idiosyncratic reaction to zolpidem resulting from GABAA receptor subunit mutation leading to altered sensitivity and affinity toward zolpidem. In such rare patients, we wonder if there could have been zolpidem-related rise in central apneas, causing a secondary rise in baseline AHI similar to the phenomenon of treatment-emergent central sleep apnea (TECSA) or could there be a higher chance of development of TECSA in patients undergoing CPAP titration with use of zolpidem? This is plausible given that NBSH creates a favorable sleep architecture allowing consolidated sleep, creating the environment and opportunity for rapid and aggressive uptitrations which otherwise would have been slow and cautious in OSA patients with insomnia.[29],[30] More experimental research into polysomnographic effects of zolpidem is needed to answer these questions definitively.

On the other end of the spectrum, some studies demonstrated an effective reduction in AHI, when NBSH was used compared to patients who used placebo or did not use any medications. Again, this could be indicative of night-to-night variability described above.[27] Slow-wave sleep has been found to profoundly reduce obstructive events (and hence AHI), especially in patients with OSA.[31] However, the effects of zolpidem on slow-wave sleep have been inconsistent so far with some studies reporting a reduction,[32] some reporting an elevation [33] and some reporting no change [34],[35],[36] in amount of slow-wave sleep in a hypnogram when patients are exposed to zolpidem. The way zolpidem affects the proportion of slow-wave sleep in a particular patient could in part explain the secondary rise or fall in AHI with use of the NBSH medications. Administration of placebo medications can also subjectively improve sleep quality and efficiency with somewhat favorable projections on polysomnographic variables as evidenced by previous studies, although it remains unclear if this could affect the subsequent AHI in such patients.[37] Furthermore, it has been demonstrated that zolpidem blocks the “histamine hub” that otherwise would have created arousals and wakefulness.[38] It is possible that borderline airflow decrements which along with cortical arousals may have been classified otherwise as hypopneas would not be contributing to hypopnea index anymore under altered spectral power density EEG effects mediated by zolpidem.[39] More research work is required to better understand the convoluted role of zolpidem in altering the baseline AHI.

Conclusion

The majority of patients using NBSH did not develop any polysomnographically evident worsening of existing AHI when using NBSH, regardless of their baseline AHI values (mild, moderate, severe, or no OSA). On the contrary, use of NBSH in many cases may even result in a marginal improvement in baseline AHI, when compared to no medications or placebo groups. On average, the AHI improved minimally with NBSH and eszopiclone showed the largest difference in AHI with an MD of − 5.73 events/h.